Serum iron variation is circadian-regulated and linked to the harmonic circadian oscillations of erythropoiesis and hepaticTfrcexpression in mice

Abstract

AbstractSerum iron has long been thought to exhibit diurnal variation and is subsequently considered an unreliable biomarker of systemic iron status. Circadian regulation (endogenous ∼24-hour periodic oscillation of a biologic function) governs many critical physiologic processes. It is unknown whether serum iron levels are regulated by circadian machinery; likewise, the circadian nature of key players of iron homeostasis is unstudied. Here we show that serum iron, hepatic transferrin receptor (TFR1) gene (Tfrc) expression and erythropoietic activity exhibit circadian rhythms. Daily oscillations of serum iron, hepaticTfrcexpression and erythropoietic activity are maintained in mice housed in constant darkness, where oscillation reflects an endogenous circadian period. Oscillations of serum iron, hepaticTfrcand erythropoietic activity were ablated when circadian machinery was disrupted inBmal1knockout mice. Interestingly, we find that circadian oscillations of erythropoietic activity and hepaticTfrcexpression are maintained in opposing phase, likely allowing for optimised usage and storage of serum iron whilst maintaining adequate serum levels. This study provides the first confirmatory evidence that serum iron is circadian regulated and uncovers liver-specific circadian regulation of TFR1, a major player in cellular iron uptake.